Novel process for the preparation of substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone

ABSTRACT

Substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, a compound of formula (1), is prepared by a novel route, which comprises reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, a compound of formula (2), or its acid addition salt with a compound of formula (3) (YCOZ) wherein Y and Z are selected from X, CC13CO, 1-imidazolyl or substituted imidazolyl, and OR; wherein X is a halide, preferably chloride, and R is selected from substituted or unsubstituted linear, branched or cyclic alkyl and aryl or heteroaryl radicals. The compound of formula (2) is prepared by treating 2-[(3,5-Dimethylphenoxy)methyl]oxirane with ammonia to yield compound of formula (2), and optionally purifying compound of formula (2) by converting to its acid addition salt.

FIELD OF THE INVENTION

The present invention relates to a novel process for preparingsubstantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, acompound of formula 1. 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone,commonly known as metaxalone (INN Name), a compound of formula 1 isindicated as an adjunct to rest, physical therapy and other measures forthe relief of discomforts associated with acute, painful musculoskeletalconditions.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 3,062,827 generically claims5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone. This patent alsodiscloses three methods for the preparation of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, viz.

-   -   (a) reacting 3-(3,5-dimethylphenoxy)-1,2-propanediol with urea;        or    -   (b) reacting 3-(3,5-dimethylphenoxy)-1-chloro-2-propanol with        urea; or    -   (c) reacting        3-(3,5-dimethylphenoxy)-2-hydroxy-1-propyl-carbamate with urea.

The patent exemplifies the process at elevated temperature i.e. 195-200°C. and also involves distillation of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone under high vacuum andtemperature. This patent does not disclose the purity of the prepared5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone; the process described isenergy consuming and yields 79% product. When we carried out thepatented process the purity of the crude product obtained was only about51% and unreacted 3-(3,5-dimethylphenoxy)-1,2-propanediol was found tobe the major impurity. There is thus a need for a process wherein thestarting material is efficiently converted to5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone.

U.S. Pat. No. 3,446,814 claims a method of preparing5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone by reacting triglycidylisocyanurate with m-xylenol The patent exemplifies reacting the rawmaterials with pulverized sodium hydroxide in chlorobenzene at itsreflux temperature which is 131-132° C. for 13 hours in presence ofbenzyltrimethylammonium chloride, followed by recrystallization of theproduct from chlorobenzene. This patent does not disclose the purity of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone. The process is alsoenergy consuming and yields 76% product.

A novel process has been found for the preparation of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone from3-(3,5-dimethylphenoxy)-2-hydroxypropylamine. None of the methodsdisclosed in prior art prepare5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone by the process of thepresent invention. The novel process converts the starting material tothe intended product in an efficient manner such that substantially allof the starting material is converted to the intended product.

OBJECT OF THE INVENTION

The object of the present invention is to provide a novel process toprepare 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone.

The process of the present invention provides a novel process thatprepares 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone in high yields ina substantially pure form.

Another object of the present invention is to provide substantially pure3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, orits acid addition salt and the process of its preparation.

SUMMARY OF INVENTION

The present invention provides a novel process for the preparation of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, compound of formula 1,comprising

reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound offormula 2, or its acid addition salt with a compound of formula 3,

wherein Y and Z are selected from X, CCl₃CO, 1-imidazolyl or substitutedimidazolyl and OR; wherein X is a halo radical, and R is selected from asubstituted or unsubstituted linear, branched or cyclic alkyl radical,and aryl or heteroaryl radical.

The process of the present invention also provides for the purificationof 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone, compound of formula 1,by crystallization of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone(formula 1) from an organic solvent system.

Particularly, the process of the preparation of compound of formula 1comprises treating compound of formula 5 with a source of ammonia toyield compound of formula 2, optionally purifying compound of formula 2by converting to its acid addition salt; and

reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound offormula 2, or its acid addition salt with a compound of formula 3.

More particularly the process of the present invention for thepreparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone encompasses

-   -   (a) reacting 3,5-dimethylphenol, compound of formula 4, with        epichlorohydrin and a base to obtain an oxirane, compound of        formula 5;    -   (b) treating compound of formula 5 with a source of ammonia to        yield compound of formula 2, optionally purifying compound of        formula 2 by converting to its acid addition salt; and    -   (c) reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine,        compound of formula 2, or its acid addition salt with a compound        of formula 3.

The present invention also provides a substantially pure3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, orits acid addition salt and the process of its preparation comprisingtreating compound of formula 5 with a source of ammonia to yieldcompound of formula 2, optionally purifying compound of formula 2 byconverting to its acid addition salt.

The novel process of the present invention has been found to beadvantageous in that the reactions involved can be carried out withoutsubstantial expenditure of energy, and the desired product, viz.5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) can beobtained in high yields in a substantially pure form.

As referred to herein substantially pure5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone is5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone with purity greater than99%.

Preferably the substantially pure5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone has purity greater than99.5%, more preferably greater than 99.9% by HPLC.

Most preferably, substantially pure5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) has a puritygreater than 99.5% and has no individual impurity that is more than0.05% by HPLC.

As referred to herein substantially pure3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, is3-(3,5-dimethylphenoxy)-2-hydroxypropylamine with purity greater than99% by HPLC.

DETAILED DESCRIPTION OF THE INVENTION

A novel method of preparation was conceived and developed by us so as toobtain substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone(formula 1).

The process of the present invention adopts a novel methodology toprepare 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone which comprisesreacting, 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, a compound offormula 2, or its acid addition salt with compound of formula 3,

wherein Y and Z are selected from X, CCl₃CO, 1-imidazolyl or substitutedimidazolyl, and OR; wherein X is a halo radical, and R is selected froma substituted or unsubstituted linear, branched or cyclic alkyl radical,and aryl or heteroaryl radical.

The substitutions on linear, branched or cyclic alkyl radical compriseof cyano, nitro, alkoxy, aryloxy, mercaptoalkyl, mercaptoaryl, alkyl orarylsulphonyl. The preferred substitutions are the electron withdrawingsubstituents like cyano or nitro.

The substitutions on aryl, heteroaryl or imidazolyl radical comprise ofhalo, cyano, nitro, alkoxy, aryloxy, mercaptoalkyl, mercaptoaryl, alkylor arylsulphonyl. The preferred substitutions are the electronwithdrawing substituents like halo, cyano or nitro.

In preferred embodiments, the compound of formula 3 is preferably acarbonate or a haloformate, most preferably a chloroformate.

The present invention also discloses a method for the preparation of3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2,which comprises treating compound of formula 5 with a source of ammoniato yield compound of formula 2, and optionally converting compound offormula 2 to its acid addition salt in order to isolate substantiallypure compound of formula 2.

The acid addition salt of compound of formula 2 may be selected from itshydrochloride, sulfate or hydrobromide salt, preferably itshydrochloride salt, in order to isolate substantially pure form compoundof formula 2.

As referred to herein substantially pure3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, is3-(3,5-dimethylphenoxy)-2-hydroxypropylamine with purity greater than99%.

Details of each step are as given below:

Preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone

According to the process of the present invention, preparation of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone is carried out by reacting3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound of formula 2, orits acid addition salt in an organic solvent in the presence of a base,with a compound of formula 3,

wherein Y and Z are selected from X, CCl₃CO, 1-imidazolyl or substitutedimidazolyl, and OR; wherein X is a halo radical, and R is selected froma substituted or unsubstituted linear, branched or cyclic alkyl radical,and aryl or heteroaryl radical.

In preferred embodiments of the invention the compound of formula 3 is acarbonate or a haloformate wherein Y is halo and Z is OR wherein R isselected from linear C₁ to C₄ alkyl radical, preferably a chloroformate,most preferably ethyl chloroformate.

The organic solvent is selected from polar and non-polar solventscomprising of aliphatic, cyclic or aromatic substituted or unsubstitutedhydrocarbons such as benzene, toluene, xylene, cyclohexane,dichloromethane, dichloroethane, monochlorobenzene and the like; ketonessuch as acetone, methlyisobutylketone, methylethylketone, cyclohexanoneand the like; cyclic and acyclic ethers such as ether, tetrahydrofuran,dioxan, dimethoxyethane, diglyme and the like; polyethers such aspoly(alkylene glycol)s and the like; nitriles such as acetonitrile,benzonitrile and the like; amides such as dimethylformamide,dimethylacetamide and the like. The preferred solvent is an aliphatic,cyclic or aromatic substituted or unsubstituted hydrocarbon, mostpreferably toluene.

The base for the reaction is selected from a group of organic orinorganic bases. The organic base may be selected from tertiary aminesor aromatic bases, and the inorganic base may be selected frombicarbonates, carbonates, hydrides, hydroxides and oxides of alkali oralkaline earth metals. In preferred embodiments the base is an inorganicbase, which is a carbonate of an alkali metal, the most preferred basebeing potassium carbonate.

In the process of the present invention, when the reaction is carriedout using an inorgainc base, addition of a facilitator has been found tobe very advantageous. The facilitator is a substance that has theproperty to complex or solvate metal cations, for example, a polyether.Alternatively, the facilitator may be a substance that can

-   -   exchange the metal cations with hydrophobic cations, for        example, a quaternary ammonium salt or a quaternary ammonium        hydroxide where substituents on the nitrogen are selected from        alkyl or aralkyl groups, for example, benzyltrialkylammonium        halide; or    -   act in a fashion similar to phase transfer catalyst.

The facilitator may be selected from cyclic and acyclic polyethers.Cyclic ethers such as crown ethers and acyclic ethers such aspoly(alkylene glycol) may be used. Poly(alkylene glycol) which may beused is poly(ethylene glycol) (PEG) with an average molecular weight inthe range between 200 to 10,000, the most preferred facilitator for thereaction being PEG400.

The reaction can be performed at temperatures ranging from 0 to 150° C.for about 1 to 10 hours, preferably at 50 to 150° C. for about 2 to 8hours, the most preferred being about 100 to 110° C. for about 5 hours.

For instance, the reaction is carried out by heating gradually to refluxa mixture of compound of formula 2, PEG-400 and an alkali metalcarbonate in an organic solvent, cooled to ambient temperature and thenethyl chloroformate is added to it. The mixture is then heated forcompletion, to furnish the desired oxazolidinone (formula 1). Thereaction mixture is worked up by standard methods known to those skilledin the art. The product is isolated with a yield of about 90%, and isgreater than 99% pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone.

Optional Further Purification of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone

In another embodiment of the process of the present invention5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is purified togreater than 99% purity to yield substantially pure5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) byrecrystallization from a solvent, optionally by addition of a secondsolvent.

The solvent system which may be used in the purification step maycomprise a mixture of solvents selected from a polar and non-polarorganic solvent comprising of aliphatic, cyclic or aromatic substitutedor unsubstituted hydrocarbons such as benzene, toluene, xylene,cyclohexane, dichloromethane, dichloroethane, monochlorobenzene and thelike; alcohols such as C₁-C₆ alcohols like methanol, ethanol, propanols,butanols and the like; diols, polyols selected from ethylene glycol,propylene glycol and the like; esters such as ethyl acetate, butylacetate and the like; ketones such as acetone, methlyisobutylketone,methylethylketone, cyclohexanone and the like; cyclic and acyclic etherssuch as ether, tetrahydrofuran, dioxan, dimethoxyethane, diglyme and thelike; polyethers such as poly(alkylene glycol) and the like; nitrilessuch as acetonitrile, benzonitrile and the like; amides such asdimethylformamide, dimethylacetamide and the like, sulfoxides such asdimethyl sulfoxide and the like. The preferred solvent system mixturefor purification to achieve substantially pure5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone is a mixture comprisingacetone and toluene, in the ratio ranging from 0.5:1.0 to 1:10, mostpreferably in the ratio 1:1.

Preferably, for recrystallization, the dissolution is carried out atabout ambient to 110° C., more preferably about 50 to 80° C.

Optionally, to the clear solution may be added another solvent andcooled gradually or spontaneously to about 0 to 30° C., preferably to 15to 25° C.

The crystallized product is filtered, washed with a solvent and driedusing conventional techniques known to those skilled in the art to yieldsubstantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone withpurity greater than 99.9% by HPLC.

The substantially pure 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone haspurity greater than 99.5% and has no individual impurity that is morethan 0.05% by HPLC.

In the preferred process of the present invention crystallization isallowed to occur by chilling or seeding or scratching the glass of thereaction vessel or cooling and other such common techniques, preferablycooling.

The product may be dried using different techniques of drying like fluidbed drying, tray drying and rotatory drying techniques with or withoutapplication of vacuum and/or under inert conditions.

Preparation of 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine Step(a)—Preparation of 3-[(3,5-dimethylphenoxy)methyl]oxirane

According to the process of the present invention step (a) is carriedout by reacting 3,5-dimethylphenol with epichlorohydrin and a base in asolvent, optionally in the presence of a facilitator.

The facilitator may be selected from quaternary ammonium salts such asbenzyltrimethylammonium chloride and the like, or from cyclic andacyclic polyethers. Cyclic ethers such as crown ethers and acyclicethers such as poly(alkylene glycol) may be used. Poly(alkylene glycol)which may be used is poly(ethylene glycol) (PEG) with an averagemolecular weight in the range between 200 to 10,000, preferably 200 to1000, the most preferred being 400.

The solvent for the reaction could be an aliphatic, cyclic or aromaticsubstituted or unsubstituted hydrocarbons such as benzene, toluene,xylene, cyclohexane, dichloromethane, dichloroethane, monochlorobenzeneand the like. In preferred embodiment, the solvent is a polar solventcomprising of cyclic and acyclic ethers such as ether, tetrahydrofuran,dioxan, dimethoxyethane, diglyme and the like; polyethers such aspoly(alkylene glycol)s (PEG) such as PEG-200, PEG-400 and the like;nitriles such as acetonitrile, benzonitrile and the like; amides such asdimethylformamide, dimethylacetamide and the like, sulfoxides such asdimethyl sulfoxide and the like. In the present invention the preferredsolvent is a water soluble ether, most preferably PEG-400, wherein noadditional facilitator is required.

The base used could be selected from an organic or inorganic base,preferably an inorganic base selected from bicarbonates, carbonates,hydrides, hydroxides and oxides of alkali or alkaline earth metals. Mostpreferably the base is potassium hydroxide.

Further, the reaction may be carried out at about 20 to 80° C. Thepreferred temperature of step (a) may be 25 to 60° C., the mostpreferred being 35 to 45° C.

The reaction may be carried out in poly(ethylene glycol)-400 in thepresence of a base.

The reaction may be carried out in poly(ethylene glycol)-400 in thepresence of potassium hydroxide at 35 to 45° C.

The reaction mixture is worked up by standard methods known to thoseskilled in the art.

Step (b)—Preparation of 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine

According to the process of the present invention step (b) is carriedout by reacting 2-[(3,5-dimethylphenoxy)methyl]oxirane with ammonia,preferably in a solvent. Ammonia could be used in the form of liquorammonia, liquid ammonia or ammonia gas.

According to one embodiment of the present invention the organic solventis selected from polar solvents like; alcohols such as C₁-C₆ alcoholslike methanol, ethanol, propanols, butanols and the like; diols, polyolsselected from ethylene glycol, propylene glycol and the like; ketonessuch as acetone, methlyisobutylketone, methylethylketone, cyclohexanoneand the like; cyclic and acyclic ethers such as ether, tetrahydrofuran,dioxan, dimethoxyethane, diglyme and the like; polyethers such aspoly(alkylene glycol)s and the like; nitriles such as acetonitrile,benzonitrile and the like; amides such as dimethylformamide,dimethylacetamide and the like, sulfoxides such as dimethyl sulfoxideand the like. When liquor ammonia is used polar water soluble solventsare preferred.

In a preferred embodiment of the present invention organic solvent is analkanol selected from C₁ to C₄ alkanol or its admixture with water. Morepreferably the alkanol is methanol.

Preferably, step (a) is carried out by adding a solution of2-[(3,5-dimethylphenoxy)methyl]oxirane in methanol to a stirred solutioncontaining large molar excess of liquor ammonia and methanol slowly overa period of about 9 hours while maintaining the temperature of about 25to 30° C.

The reaction mixture is worked up by standard methods known to thoseskilled in this art. For instance, in a specific embodiment aftercompletion of reaction methanol was distilled out below 60° C. undervacuum. The product was extracted into methylene dichloride and theorganic extract was acidified with conc. HCl added till about pH 2 toprecipitate the product selectively as a hydrochloride salt devoid ofimpurities, which could be easily filtered to get 99% pure3-(3,5-dimethylphenoxy)-2-hydroxypropylamine hydrochloride.

The invention is illustrated but not restricted by the description inthe following example.

EXAMPLES Example-1 (a) Preparation of2-[(3,5-Dimethylphenoxy)methyl]oxirane (Formula 5)

To a stirred solution of 3,5-dimethylphenol (10 g, 0.818 mol.), PEG-400(300 ml), epichlorohydrin (128.01 ml, 1.63 mol) at 25-30° C. is addedone part of potassium hydroxide (18.37 g, 0.32 mol.). Two more lots ofpotassium hydroxide (18.37 g each, 0.64 mol.) are charged, each after anhour's interval after cooling the mixture to 25-30° C. The mixture wasthen stirred further for an hour of at 35-45° C. Water (400 ml) isslowly added and the product is extracted into hexane (2×200 ml) and(1×100 ml). The combined hexane extract is concentrated at 60-65° C.under vacuum. Any excess epichlorohydrin in the residue is finallystripped off by adding toluene (50.0 ml) and degassing at 60-65° C.under vacuum. Yield of the product is 142.0 g.

(b) Preparation of 3-(3,5-Dimethylphenoxy)-2-hydroxypropylaminehydrochloride (Formula 2)

A solution of 2-[(3,5-dimethylphenoxy)methyl]oxirane (100.0 g, 0.561mol) in methanol (300.0 ml) is added slowly during about 9 hrs, to astirred solution containing liquor ammonia (1150 ml) and methanol (700ml) while maintaining the temperature between 25-30° C. After completionof addition, the mixture is stirred for a further 1 hr and the methanolwas distilled out under reduced pressure at below 60° C. The product isthen extracted into methylene dichloride (1×300 ml. & 1×200 ml.). Pooledextracts are washed with water (2×250 ml). The organic layer is driedover anhydrous sodium sulfate, cooled to 5-10° C. and conc. HCl is addeduntil the pH is about 2.0. The precipitated hydrochloride salt isfiltered, washed successively with methylene dichloride (100.0 ml) andhexane (50.0 ml). Product is finally dried in air oven at 75-80° C. toyield 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine hydrochloride, 62.0 g(purity>99.0%)

(c) Preparation of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone(Formula 1)

A mixture of PEG400 (50 ml), toluene (500 ml), potassium carbonatepowder (89.6 g, 0.648 mol), and3-(3,5-dimethylphenoxy)-2-hydroxypropylamine hydrochloride (formula 3)(50 g, 0.216 mol) is heated gradually to reflux during 1.0 hr., and thenazeotropically refluxed for 3 hrs. The mixture is then cooled to 25-30°C. and ethyl chloroformate (formula 4) (24.8 g, 0.228 mol.) is addedgradually during 6 hrs. while maintaining the temperature below 40° C.during the addition. The reaction mixture is then heated at 50-55° C.for 2 hours. The temperature is raised to reflux and then refluxedazeotropically for 5.0 hrs using Dean-Stark condenser. The mixture isthen cooled to 10-15° C., water (150 ml) is added and the pH is adjustedto 6.5-7.0 by gradual addition of conc. HCl. After stirring at 10-15° C.for 1 hr. the product is separated by filtration and washed with toluene(2×25 ml), followed by water until washings are free from chloride, anddried. The toluene layer from the filtrates is separated, washed withwater (2×100 ml). It is concentrated to one tenth of the volume, cooledto 25-30° C. and the crystallized second crop is filtered. Yield ofproduct 43.0 g (90%, purity>99% by HPLC).

(d) Purification of 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone(Formula 1)

5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1), (5 g)obtained in example 1(c) is dissolved in acetone (15 ml) by heating to60-65° C. To the clear solution is added toluene (15 ml), cooledgradually to 20-25° C. and stirred for 2 hrs. at this temperature. Thecrystallized product is filtered, washed with toluene (5 ml) and driedto get 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) withpurity of 99.93% (having a maximum single impurity of 0.02%).

Example 2 Method for Analysis of Purity by HPLC Buffer

Dissolve 1.36 g potassium dihydrogenorthophosphate in 1000 ml of water.Take 650 ml of buffer add 2 ml of triethylamine. Adjust pH to 2.5 byorthophosphoric acid.

Mobile Phase:

Mix buffer solution and acetonitrile in the ratio of 650:350. Filter anddegas prior to use.

Sample Preparation:

Transfer about 100 mg accurately weighed sample into a 100 ml volumetricflask. Dissolve in and dilute upto mark with mobile phase.

System Suitability Solution:

Transfer about 10 mg of metaxalone into a 100 ml volumetric flask.Dissolve in and dilute upto mark with mobile phase.

Chromatographic System:

The liquid chromatograph is equipped with a 225 nm UV detector and 25cm×4.6 mm, 5 micron column that contains Hypersil BDS C8. The flow rateis about 1.0 ml/min.

Procedure:

Inject 10 ml of system suitability solution into the system and recordthe chromatograms upto 25 min. Calculate the tailing factor ofmetaxalone peak. It should not be more than 1.5 and number oftheoretical plates should not be less than 5000.

Inject 10 ml of sample preparation into the system and record thechromatograms upto 25 min. The retention time of metaxalone is 13 min.Calculate the amount of related substances by area normalization method,while disregarding any peak with an area percentage less than 0.025.

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 28. A novel process for the preparation of5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) comprising

reacting 3-(3,5-dimethylphenoxy)-2-hydroxypropylamine, compound offormula 2, or its acid addition salt with a compound of formula 3,

wherein Y and Z are selected from X, CCl ₃CO, 1-imidazolyl orsubstituted imidazolyl, and OR: wherein X is a halo radical, and R isselected from a substituted or unsubstituted linear, branched or cyclicalkyl radical, and aryl or heteroaryl radical.
 29. A process as claimedin claim 28 wherein the reaction is carried out in the presence of abase.
 30. A process as claimed in claim 29 wherein the base is potassiumcarbonate . . .
 31. A process as claimed in claim 28 wherein in thecompound of formula 3 Y is a halo radical and Z is OR wherein is alinear C₁ to C₄ alkyl radical.
 32. A process claimed in claim 31 whereinthe compound of formula 3 is ethyl chloroformate.
 33. A process asclaimed in claim 28 wherein the reaction is carried out in the presenceof a facilitator.
 34. A process as claimed in claim 33 wherein thefacilitator is selected from cyclic and acyclic polyethers.
 35. Aprocess as claimed in claim 34 wherein the facilitator is poly(ethyleneglycol) with an average molecular weight in the range between 200 to10,000.
 36. A process as claimed in claim 28 wherein the molar ratio ofcompound of formula 2 to compound of formula 3 is in the range of about1:0.8 to 1:1.5.
 37. A process as claimed in claim 28 wherein the5-(3,5-dimethylphenoxy)methyl 2-oxazolidinone (formula 1) is obtained ina substantially pure form and has a purity greater than 99%.
 38. Aprocess for purifying 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone(formula 1) by crystallizing5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) from anorganic solvent system.
 39. A process as claimed in claim 38 wherein the5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained ina substantially pure form and has a purity greater than 99.5%.
 40. Aprocess as claimed in claim 38 wherein the5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained ina substantially pure form has a purity greater than 99.9%.
 41. A processas claimed in claim 38 wherein the5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone (formula 1) is obtained ina substantially pure form and his a purity greater than 99.5% and noindividual impurity that is more t 0.05%.
 42. A process as claimed inclaim 38 wherein the organic solvent system is a mixture of acetone andtoluene.
 43. A process as claimed in claim 42 wherein the volume ratioof acetone toluene is about 0.5:1.0 to 1:10.